Resonant Inelastic X-Ray Scattering Reveals Hidden Local Transitions of the Aqueous OH Radical.

Resonant inelastic x-ray scattering (RIXS) provides remarkable opportunities to interrogate ultrafast dynamics in liquids. Here we use RIXS to study the fundamentally and practically important hydroxyl radical in liquid water, OH(aq). Impulsive ionization of pure liquid water produced a short-lived population of OH(aq), which was probed using femtosecond x-rays from an x-ray free-electron laser. We find that RIXS reveals localized electronic transitions that are masked in the ultraviolet absorption spectrum by strong charge-transfer transitions-thus providing a means to investigate the evolving electronic structure and reactivity of the hydroxyl radical in aqueous and heterogeneous environments. First-principles calculations provide interpretation of the main spectral features.

Postoperative radiotherapy provides better local control and long-term outcome in selective cases of cutaneous squamous cell carcinoma with perineural invasion.

BACKGROUND: Perineural invasion (PNI) is a feature of poor prognosis in cutaneous squamous cell carcinoma (CSCC). The benefit of postoperative radiotherapy (PORT) in the management of CSCC with PNI is still not well established. OBJECTIVES: We aimed to evaluate the usefulness of PORT in the treatment of CSCC with PNI so as to determine which patients would best benefit from this type of treatment. METHODS: A retrospective multicenter cohort of 110 CSCCs with PNI was evaluated. Eighteen recurrent cases were excluded for subsequent analysis. We searched for the types of PNI associated with poor outcome and analysed the effectiveness of PORT on different groups of CSCC with PNI. We also assessed for the usefulness of PORT depending on the surgical margin status (either clear or positive). RESULTS: Postoperative radiotherapy showed clear benefit over observation in CSCC with PNI and positive margins after surgery, where the management by observation increased the risk of poor outcome events 2.43 times (P = 0.025), and especially in those with positive margins and PNI ≥0.1 mm, where the risk of poor prognosis is eight times greater following a management by observation (P = 0.0065). Multivariate competing risk analysis preserved statistical significance. CONCLUSIONS: The use of PORT on patients with CSCC with PNI and positive margins after surgery, especially in PNI ≥0.1 mm, significantly improves long-term outcome. The benefit of PORT in cases with clear margins is not as evident, especially in those with PNI of small-calibre nerves. Clinical trials are imperative.

Femtosecond electronic response of atoms to ultra-intense X-rays.

An era of exploring the interactions of high-intensity, hard X-rays with matter has begun with the start-up of a hard-X-ray free-electron laser, the Linac Coherent Light Source (LCLS). Understanding how electrons in matter respond to ultra-intense X-ray radiation is essential for all applications. Here we reveal the nature of the electronic response in a free atom to unprecedented high-intensity, short-wavelength, high-fluence radiation (respectively 10(18) W cm(-2), 1.5-0.6 nm, approximately 10(5) X-ray photons per A(2)). At this fluence, the neon target inevitably changes during the course of a single femtosecond-duration X-ray pulse-by sequentially ejecting electrons-to produce fully-stripped neon through absorption of six photons. Rapid photoejection of inner-shell electrons produces 'hollow' atoms and an intensity-induced X-ray transparency. Such transparency, due to the presence of inner-shell vacancies, can be induced in all atomic, molecular and condensed matter systems at high intensity. Quantitative comparison with theory allows us to extract LCLS fluence and pulse duration. Our successful modelling of X-ray/atom interactions using a straightforward rate equation approach augurs favourably for extension to complex systems.

Guest-host interactions investigated by time-resolved X­ray spectroscopies and scattering at MHz rates: solvation dynamics and photoinduced spin transition in aqueous Fe(bipy)3(2+).

We have studied the photoinduced low spin (LS) to high spin (HS) conversion of [Fe(bipy)(3)](2+) in aqueous solution. In a laser pump/X-ray probe synchrotron setup permitting simultaneous, time-resolved X-ray diffuse scattering (XDS) and X-ray spectroscopic measurements at a 3.26 MHz repetition rate, we observed the interplay between intramolecular dynamics and the intermolecular caging solvent response with better than 100 ps time resolution. On this time scale, the initial ultrafast spin transition and the associated intramolecular geometric structure changes are long completed, as is the solvent heating due to the initial energy dissipation from the excited HS molecule. Combining information from X-ray emission spectroscopy and scattering, the excitation fraction as well as the temperature and density changes of the solvent can be closely followed on the subnanosecond time scale of the HS lifetime, allowing the detection of an ultrafast change in bulk solvent density. An analysis approach directly utilizing the spectroscopic data in the XDS analysis effectively reduces the number of free parameters, and both combined permit extraction of information about the ultrafast structural dynamics of the caging solvent, in particular, a decrease in the number of water molecules in the first solvation shell is inferred, as predicted by recent theoretical work.

Unveiling and driving hidden resonances with high-fluence, high-intensity x-ray pulses.

We show that high fluence, high-intensity x-ray pulses from the world's first hard x-ray free-electron laser produce nonlinear phenomena that differ dramatically from the linear x-ray-matter interaction processes that are encountered at synchrotron x-ray sources. We use intense x-ray pulses of sub-10-fs duration to first reveal and subsequently drive the 1s↔2p resonance in singly ionized neon. This photon-driven cycling of an inner-shell electron modifies the Auger decay process, as evidenced by line shape modification. Our work demonstrates the propensity of high-fluence, femtosecond x-ray pulses to alter the target within a single pulse, i.e., to unveil hidden resonances, by cracking open inner shells energetically inaccessible via single-photon absorption, and to consequently trigger damaging electron cascades at unexpectedly low photon energies.

Time-resolved pump-probe experiments at the LCLS.

The first time-resolved x-ray/optical pump-probe experiments at the SLAC Linac Coherent Light Source (LCLS) used a combination of feedback methods and post-analysis binning techniques to synchronize an ultrafast optical laser to the linac-based x-ray laser. Transient molecular nitrogen alignment revival features were resolved in time-dependent x-ray-induced fragmentation spectra. These alignment features were used to find the temporal overlap of the pump and probe pulses. The strong-field dissociation of x-ray generated quasi-bound molecular dications was used to establish the residual timing jitter. This analysis shows that the relative arrival time of the Ti:Sapphire laser and the x-ray pulses had a distribution with a standard deviation of approximately 120 fs. The largest contribution to the jitter noise spectrum was the locking of the laser oscillator to the reference RF of the accelerator, which suggests that simple technical improvements could reduce the jitter to better than 50 fs.

Auger electron angular distribution of double core-hole states in the molecular reference frame.

The Linac Coherent Light Source free electron laser is a source of high brightness x rays, 2×10(11) photons in a ∼5 fs pulse, that can be focused to produce double core vacancies through rapid sequential ionization. This enables double core vacancy Auger electron spectroscopy, an entirely new way to study femtosecond chemical dynamics with Auger electrons that probe the local valence structure of molecules near a specific atomic core. Using 1.1 keV photons for sequential x-ray ionization of impulsively aligned molecular nitrogen, we observed a rich single-site double core vacancy Auger electron spectrum near 413 eV, in good agreement with ab initio calculations, and we measured the corresponding Auger electron angle dependence in the molecular frame.

Observation of the fastest chemical processes in the radiolysis of water.

Elementary processes associated with ionization of liquid water provide a framework for understanding radiation-matter interactions in chemistry and biology. Although numerous studies have been conducted on the dynamics of the hydrated electron, its partner arising from ionization of liquid water, H2O+, remains elusive. We used tunable femtosecond soft x-ray pulses from an x-ray free electron laser to reveal the dynamics of the valence hole created by strong-field ionization and to track the primary proton transfer reaction giving rise to the formation of OH. The isolated resonance associated with the valence hole (H2O+/OH) enabled straightforward detection. Molecular dynamics simulations revealed that the x-ray spectra are sensitive to structural dynamics at the ionization site. We found signatures of hydrated-electron dynamics in the x-ray spectrum.

The Polish Genetic Database of Victims of Totalitarianisms.

This paper describes the creation of the Polish Genetic Database of Victims of Totalitarianism and the first research conducted under this project. On September 28th 2012, the Pomeranian Medical University in Szczecin and the Institute of National Remembrance-Commission for Prosecution of Crimes against the Polish Nation agreed to support the creation of the Polish Genetic Database of Victims of Totalitarianism (PBGOT, www.pbgot.pl). The purpose was to employ state-of-the-art methods of forensic genetics to identify the remains of unidentified victims of Communist and Nazi totalitarian regimes. The database was designed to serve as a central repository of genetic information of the victim's DNA and that of the victim's nearest living relatives, with the goal of making a positive identification of the victim. Along the way, PGBOT encountered several challenges. First, extracting useable DNA samples from the remains of individuals who had been buried for over half a century required forensic geneticists to create special procedures and protocols. Second, obtaining genetic reference material and historical information from the victim's closest relatives was both problematic and urgent. The victim's nearest living relatives were part of a dying generation, and the opportunity to obtain the best genetic and historical information about the victims would soon die with them. For this undertaking, PGBOT assembled a team of historians, archaeologists, forensic anthropologists, and forensic geneticists from several European research institutions. The field work was divided into five broad categories: (1) exhumation of victim remains and storing their biological material for later genetic testing; (2) researching archives and historical data for a more complete profile of those killed or missing and the families that lost them; (3) locating the victim's nearest relatives to obtain genetic reference samples (swabs), (4) entering the genetic data from both victims and family members into a common database; (5) making a conclusive, final identification of the victim. PGBOT's first project was to identify victims of the Communist regime buried in hidden mass graves in the Powazki Military Cemetery in Warsaw. Throughout 2012 and 2013, PGBOT carried out archaeological exhumations in the Powazki Military Cemetery that resulted in the recovery of the skeletal remains of 194 victims in several mass graves. Of the 194 sets of remains, more than 50 victims have been successfully matched and identified through genetic evidence.

Hetero-site-specific X-ray pump-probe spectroscopy for femtosecond intramolecular dynamics.

New capabilities at X-ray free-electron laser facilities allow the generation of two-colour femtosecond X-ray pulses, opening the possibility of performing ultrafast studies of X-ray-induced phenomena. Particularly, the experimental realization of hetero-site-specific X-ray-pump/X-ray-probe spectroscopy is of special interest, in which an X-ray pump pulse is absorbed at one site within a molecule and an X-ray probe pulse follows the X-ray-induced dynamics at another site within the same molecule. Here we show experimental evidence of a hetero-site pump-probe signal. By using two-colour 10-fs X-ray pulses, we are able to observe the femtosecond time dependence for the formation of F ions during the fragmentation of XeF2 molecules following X-ray absorption at the Xe site.

Back-pack mice as a model of renal mesangial IgA dimers deposition.

Mesangial IgA in IgA nephropathy are dimers with a J chain but no poly-Ig receptor. This molecular structure has led to the hypothesis that these IgA are issued from the lamina propria of mucosal areas, reaching the kidney by way of the peripheral blood. The availability of hybridomas producing IgA dimers provided an opportunity to test this hypothesis in a new experimental model of IgA nephropathy. Mice were injected subcutaneously (back-pack mice) or intraperitoneally with hybridoma cells secreting either monoclonal IgA dimers, or monoclonal IgA monomers. The influence of immune complex formation was also tested in both these models. Renal IgA deposition was investigated 12 days after the injection of hybridoma cells. Backpack mice developed highly vascularized subcutaneous tumors. Mesangial IgA deposits were observed only in dimeric IgA hybridoma back-pack animals. No significant staining was observed in glomeruli from animals injected with hybridoma cells producing monomeric IgA. None of the hybridomas induced mesangial deposition when injected intraperitoneally. This animal model demonstrates the capacity of circulating IgA dimers to spontaneously form mesangial deposits and contributes to confirm the involvement of abnormalities of mucosal immunity in the pathogenesis of IgA nephropathy.

Anti-myelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis.

Humoral auto-immunity to the myelin oligodendrocyte glycoprotein (MOG) is likely involved in the pathogenesis of multiple sclerosis (MS). In 44 MS patients and 30 controls, Ig-producing B cells were identified by their isotype and as MOG-specific spot-forming cells (SFC). Peripheral anti-MOG antibodies were assayed in ELISA as well as anti-butyrophilin antibodies to investigate for molecular mimicry. MS patients had significantly higher levels of IgA- and MOG-SFC than controls, as well as significantly higher antibody responses to MOG and butyrophilin. These data provide added support for the implication of anti-MOG humoral immunity in the pathophysiology of MS, and suggest a balance of systemic (anti-self) and mucosal (environment-modulated) immune reactions in an attempt at regulating the pathogenic specific immune response.

Early increase of peripheral B cell levels in kidney transplant recipients with CMV infection or reactivation.

BACKGROUND: Cytomegalovirus (CMV) infection or reactivation is a frequent complication of renal transplantation. Diagnosis of these conditions relies on the detection of circulating antigen, or of specific IgM and/or IgG, which develop over several weeks. Evocative clinical features may be detected earlier, but lack specificity. Rapid and early changes in the partition of lymphocyte subsets could be an additional indication of pending CMV infection. METHODS: A systematic follow-up of peripheral B lymphocytes identified immunophenotypically by the determination of surface immunoglobulins (sIg), performed in 97 kidney transplant recipients, allowed to identify transient increases apparently predictive of CMV primo-infection or reactivation over the next 3 months. To better define the nature of these B cells, an extended investigation was performed for 14 prospective patients. In addition to surface Ig, membrane CD19, HLA-DR, and CD80 expression were explored. The cytoplasmic presence of mu, kappa, and lambda chains was also examined. B cell function was investigated using the ELISPOT technique, which allows an enumeration of the populations of IgG, IgA, and IgM secreting B cells. RESULTS: Retrospective analysis of the clinical outcome of the cohort of 97 patients evidenced that early transient increases in B cell levels were significantly (P<0.0001) associated with CMV infection. The same trend was noted in the smaller series of patients who benefited from a more extensive investigation of B cells, 10 of whom presented clinical or biological signs of CMV infection. Mature B cells, expressing surface Ig, CD19, DR, and CD80 are those presenting transient increases. No significant variation of preB (cmu+/kappalambda-) or activated (spot-forming) cells was evidenced in these patients. CONCLUSION: Individual examination of each patient's immune reconstitution profile allows to detect transient peaks of mature B cell during the initial immunosuppressive therapy, that appear to be predictive of oncoming CMV infection or reactivation.

Tuberculosis and pregnancy. Five- to ten-year review of 215 patients in their fertile age.

This study evaluated the influence of pregnancy as a relapse factor in pulmonary tuberculosis in 215 patients who recieved adequate chemotherapy. A comparison was made between the evolution of patients who had pregnancies and those who did not. On ending the period of observation (details are lacking with respect to only of observation (details are lacking with respect to only seven patients), 203 patients continued to be well without active pulmonary lesions, and no relapses had been seen. Of these patients, 100 had 149 pregnancies, giving birth to 135 children; 108 had no pregnancies. Fifteen pregnancies took place while patients were in the active phase of their tuberculosis, and 134 occurred once chemotherapy had ended; seven patients gave birth to nine children while their postchemotherapy cavity remained inactive. From the extended period of observation, it can be concluded that pregnancy, birth, puerperium, and lactation do not presuppose any risk of relapse of pulmonary tuberculosis when it is adequately treated even in patients in whom an inactive postchemotherapy cavity persisted.

Urinary estradiol-17-beta-glucuronide assay for gonadotropin therapy.

To investigate the possibility of using urinary estradiol-17 beta-glucuronide (E2-17G) measured by direct radioimmunoassay to monitor ovulation induction with human menopausal gonadotropin (hMG), serum estrogen and urinary E2-17G levels were determined daily by 21 women treated with hMG for a total of 32 treatment cycles. Urinary E2-17G was measured in 24-hour and overnight specimens. A significant correlation was found between serum estrogens (primarily estradiol) measured by radioimmunoassay without preceding chromatography and urinary E2-17G excretion measured at 24 hours and overnight. The correlation was not significantly improved by correcting the 24-hour and overnight urinary E2-17G excretion levels with creatinine measurements. Although there was significant correlation between serum estrogens and urinary E2-17G measured by direct radioimmunoassay, the urinary E2-17G concentrations observed when serum estrogens levels indicated preovulatory follicle maturation (ie, at serum estrogens levels between 500 and 1000 pg/ml) varied so much that a clinical decision to trigger or not to trigger ovulation with human chorionic gonadotropin could not be reached in each case. These data indicate that significant correlation is not the only prerequisite for a new method to replace a proved procedure. Further studies are required to determine the reliability of monitoring hMG therapy with direct E2-17G radioimmunoassays in overnight urine collections.

Cytokines, immunoglobulins, and bacterial pathogens in middle ear effusions.

OBJECTIVE: To elucidate the role of cytokines, immunoglobulins, and bacterial pathogens in the middle ear effusions (MEEs) of children with otitis media (OM). DESIGN: Paired MEEs and serum samples collected from consecutive patients were assayed for immunoglobulins. Middle ear effusions were cultured for bacterial pathogens and assayed for interleukin-1 beta, interleukin-6, tumor necrosis factor alpha, and interferon gamma. The medical charts of the patients were retrospectively reviewed to define the history of OM. SUBJECTS: Seventy-five patients with a history of recurrent acute OM, persistent OM with effusion, or both. Exclusion criteria included the presence of a major coexisting condition, or an unclear or atypical history of OM. SETTING: A private practice at a tertiary care children's hospital. INTERVENTIONS: At the time of tympanostomy tube placement, with the patient under general anesthesia, one MEE and a serum sample were collected. RESULTS: Interleukin-1 beta was detected in 58% (44/75) MEEs; interleukin-6, 83% (60/72); tumor necrosis factor alpha, 37% (28/75) [corrected]; and interferon gamma, 61% (45/74). Concentrations of interleukin-1 beta, interleukin-6 and tumor necrosis factor alpha in MEEs were highly correlated with each other (P < .01 for each association) suggesting increased local production and the expected effects of cytokines stimulating their own production during OM. High concentrations of tumor necrosis factor alpha in MEEs were also associated with a history of multiple placements of tympanostomy tubes (r = .63). CONCLUSIONS: These data suggest a regulatory role for cytokines in inflammation during OM, and suggest that high concentrations of tumor necrosis factor alpha in MEEs may be a marker for OM chronicity.

'A systematic overview--a decade of research'. The information and counselling needs of people with epilepsy.

This paper explores the background to epilepsy in terms of medical impact and psychosocial effects. The argument that information and counselling may be central to the person with epilepsy is explored. The evidence from primary research published between 1990 and 2000 investigating the information and counselling needs of people with epilepsy is appraised and synthesized. This paper seeks to answer the following questions: What are the information and counselling needs of people with epilepsy? What are the preferred formats, timing and delivery of information and counselling? What are the outcomes of information giving and counselling for people with epilepsy? The review suggests that there are unmet needs for personal and general information about epilepsy which may include individual or group education and counselling. Information related to gaining control for people with epilepsy and targeted public education may contribute to improved quality of life for people with epilepsy. Information is required which is individually relevant and could be delivered in small groups or as part of an individual counselling service. Specialist epilepsy clinics and specialist nurses can improve patient knowledge and communication and provide an effective and high quality service for people with epilepsy.

A systematic overview--a decade of research'. The information and counselling needs of people with epilepsy.

This paper explores the background to epilepsy in terms of medical impact and psychosocial effects. The argument that information and counselling may be central to the person with epilepsy is explored. The evidence from primary research published between 1990 and 2000 investigating the information and counselling needs of people with epilepsy is appraised and synthesized. This paper seeks to answer the following questions: What are the information and counselling needs of people with epilepsy? What are the preferred formats, timing and delivery of information and counselling? What are the outcomes of information giving and counselling for people with epilepsy? The review suggests that there are unmet needs for personal and general information about epilepsy which may include individual or group education and counselling. Information related to gaining control for people with epilepsy and targeted public education may contribute to improved quality of life for people with epilepsy. Information is required which is individually relevant and could be delivered in small groups or as part of an individual counselling service. Specialist epilepsy clinics and specialist nurses can improve patient knowledge and communication and provide an effective and high quality service for people with epilepsy.

Solvation dynamics monitored by combined X-ray spectroscopies and scattering: photoinduced spin transition in aqueous [Fe(bpy)3](2+).

We have studied the photoinduced low spin (LS) to high spin (HS) conversion of aqueous Fe(bpy)3 with pulse-limited time resolution. In a combined setup permitting simultaneous X-ray diffuse scattering (XDS) and spectroscopic measurements at a MHz repetition rate we have unraveled the interplay between intramolecular dynamics and the intermolecular caging solvent response with 100 ps time resolution. On this time scale the ultrafast spin transition including intramolecular geometric structure changes as well as the concomitant bulk solvent heating process due to energy dissipation from the excited HS molecule are long completed. The heating is nevertheless observed to further increase due to the excess energy between HS and LS states released on a subnanosecond time scale. The analysis of the spectroscopic data allows precise determination of the excited population which efficiently reduces the number of free parameters in the XDS analysis, and both combined permit extraction of information about the structural dynamics of the first solvation shell.

The 2012 derecho: emergency medical services and hospital response.

During the early afternoon of June 29, 2012, a line of destructive thunderstorms producing straight line winds known as a derecho developed near Chicago (Illinois, USA). The storm moved southeast with wind speeds recorded from 100 to 160 kilometers per hour (kph, 60 to 100 miles per hour [mph]). The storm swept across much of West Virginia (USA) later that evening. Power outage was substantial as an estimated 1,300,000 West Virginians (more than half) were without power in the aftermath of the storm and approximately 600,000 citizens were still without power a week later. This was one of the worst storms to strike this area and occurred as residents were enduring a prolonged heat wave. The wind damage left much of the community without electricity and the crippling effect compromised or destroyed critical infrastructure including communications, air conditioning, refrigeration, and water and sewer pumps. This report describes utilization of Emergency Medical Services (EMS) and hospital resources in West Virginia in response to the storm. Also reported is a review of the weather phenomena and the findings and discussion of the disaster and implications.